With sky-rocketing economic growth in Korea, senile dementia represented by Alzheimer's disease has been a social problem with the increase of the aged population. Today the Alzheimer's disease becomes more serious social and economical burden day by day.
Alzheimer's disease (referred as ‘AD’ hereinafter) is the most dominant neurodegenerative disease caused by the pathological accumulation of Aβ in brain. The unbalance between Aβ synthesis and its elimination results in the accumulation of Aβ and senile plaques (Geula C. et al., Nat. Med., 4, 827-831, (1998)). Alzheimer's dementia is divided into familial AD (FAD) attributed to genetic mutation and sporadic AD (SAD) whose causes have not been explained yet. The FAD patients took 5-10% of the total AD patients and the rest are sporadic AD patients. The causative genes for familial AD have been identified to be presenilin 1 (referred as ‘PS1’ hereinafter) on chromosome 14, amyloid precursor protein (referred as ‘APP’ hereinafter) on chromosome 21 and presenilin 2 (referred as ‘PS2’ hereinafter) on chromosome 1.
In the APP over-expressing transgenic mice, more precisely in transgenic mice over-expressing mutated ATT gene which is very common in familial AD patients, senile plaques were observed and space perception was decreased, which are characteristic symptoms of AD patients. When normal PS1 protein was over-expressed, Aβgeneration was not changed. However, in transgenic mice over-expressing mutated PS1 protein, plenty of Aβ were generated as shown in AD patients. Considering all the earlier reports, APP mutation observed in FAD patients seems to be closely related to over-production of Aβ and further responsible for AD break-out.
While studies on APP, PS1 and PS2 genes involved in overproduction of Aβ in familial AD patients have been actively progressed, studies on the effect of the reduced Aβ degradation according to aging have been unsatisfactory. In recent cell- or animal tests, it was confirmed that inhibiting the activity of neprilysin (referred as ‘NEP’ hereinafter) or insulin degrading enzyme (referred as ‘IDE’ hereinafter) results in the over-accumulation of Aβ suggesting that the decrease of the expression and functions of Aβ degrading gene might be the major cause of Aβ accumulation in aged brain. NEP or IDE mediated Aβ degradation was observed in the mouse produced by crossbreeding a transgenic mouse over-expressing NEP or IDE with a mouse over-generating Aβ.
The activation of enzymes degrading Aβ might contribute to the treatment of AD including familial AD since they can degrade Aβ whose level increases according to aging. However, it is controversial whether these proteases can degrade condensed Aβ as well. Even in a transgenic mouse over-expressing these proteases, Aβ level was still high, indicating that there is another protease which can decompose Aβ.
Various attempts have been made so far to prevent and treat AD. For example, a non-self antigen vaccine based on Aβ peptide has been used to inhibit Aβ agglutination or accumulation (WO 2001/39796), an Aβ isolating compound based on VEGF polypeptide has been used to inhibit the combination of VEGF with Aβ (WO 2003/055910), a compound inhibiting Aβ core protein generation and plaque formation based on the compound used for the treatment of Down's syndrome and senile dementia has been used for the treatment of AD (WO 1995/09838).
The present inventors have been tried to identify an enzyme which is able to degrade Aβ and have been applied for a patent with a protein inhibiting Aβ agglutination isolated from bacteria (Korean Patent Publication No. 10-2005-000007102).
As an effort to find out an enzyme degrading Aβ among human proteins, the present inventors have searched a candidate among human endogenous proteins having similar sequence with AABA (amyloid peptide aggregation blocking activity), an Aβ degrading protein, and at last selected GCP-II as a promising candidate and further examined its biological and biochemical properties. As a result, the present inventors completed this invention by confirming that the GCP-II is able to degrade not only Aβ in monomer or oligomer form but also aggregated Aβ or even Aβ in soluble, insoluble form.